Several birth defects involving lack of fusion of septa (e.g., cleft palate and cardiac septal defects) appear to involve polygenic inheritance. It is a major challenge to understand how these polygenes function. Investigations in mice have suggested that alleles at the major histocompatibility locus may be one component of this polygenic system. Two inherited biochemical traits also appear to be important in the etiology of cleft palate in mice: 1) variation in tissue levels of cyclic AMP, 2) variation in amount of glucocorticoid receptor. We propose to examine the possible role of these variables in the etiology of human septal defects. We will determine whether variation in the HLA region of chromosome 6 is a component of the polygenic inheritance of birth defects involving failure of fusion of septa. We will see if there is greater variation in lymphocyte cAMP levels between families than within families and whether a correlation between lymphocyte cAMP levels and septal defects may occur. Finally, we will determine if there is greater variation in lymphocyte steroid sensitivity between families than within families and whether a correlation of lymphocyte steroid sensitivity to septal defects may occur.